Renal Failure Increases Cardiac Histone H3 Acetylation, Dimethylation, and Phosphorylation and the Induction of Cardiomyopathy-Related Genes in Type 2 Diabetes
Renal Failure Increases Cardiac Histone H3 Acetylation, Dimethylation, and Phosphorylation and the Induction of Cardiomyopathy-Related Genes in Type 2 Diabetes
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DOI：
10.2353/ajpath.2010.090528
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发表时间：
2010-03-01
影响因子：
6
通讯作者：
Anders, Hans-Joachim
中科院分区：
文献类型：
--
作者：
Gaikwad, Anil Bhanudas;Sayyed, Sufyan G.;Anders, Hans-Joachim
糖尿病和肾衰竭的结合与加速性心肌病有关，但肾衰竭如何驱动糖尿病心脏病的分子机制仍然难以捉摸。我们推测，肾功能衰竭的代谢异常将影响心脏基因转录的表观遗传控制，并试图确定组蛋白H3修饰模式的2型糖尿病小鼠的心脏与几个程度的肾功能不全。我们研究了6个月大的非糖尿病小鼠和2型糖尿病db/db小鼠心脏中的组蛋白H3修饰和基因表达，这些小鼠在6周龄时接受了假手术或单侧肾切除术，这通过肾小球超滤加速了db/db小鼠的肾小球硬化。与肾功能正常的db/db小鼠或非糖尿病野生型小鼠相比，患有肾小球硬化、白蛋白尿和肾小球滤过率降低的单肾切除db/db小鼠的心脏的Western印迹显示心脏组蛋白H3的乙酰化（K23和9）、磷酸化（Ser 10）、二甲基化（K4）增加，二甲基化（K9）减少。这种模式表明染色质结构的改变有利于基因转录。事实上，从unine-phrectomized db/db小鼠的心脏揭示了多种心肌病相关基因的mRNA表达增加，以及心肌细胞肥大。这些数据表明，肾功能衰竭改变了心脏组蛋白H3表观遗传学，这促进了2型糖尿病的心肌细胞肥大。(Am J Pathol 2010，176：1079-1083 DOI：10.2353/ajpath.2010.090528）
The combination of diabetes and renal failure is associated with accelerated cardiomyopathy, but the molecular mechanisms of how renal failure drives diabetic heart disease remain elusive. We speculated that the metabolic abnormalities of renal failure will affect the epigenetic control of cardiac gene transcription and sought to determine the histone H3 modification pattern in hearts of type 2 diabetic mice with several degrees of renal dysfunction. We studied the histone H3 modifications and gene expression in the heart of 6-month-old nondiabetic mice and type 2 diabetic db/db mice that underwent either sham surgery or uninephrectomy at 6 weeks of age, which accelerates glomerulosclerosis in db/db mice via glomerular hyperfiltration. Western blotting of hearts from unine-phrectomized db/db mice with glomerulosclerosis, albuminuria, and reduced glomerular filtration rate revealed increased acetylation K23 and 9), phosphorylation (Ser 10), dimethylation (K4), and reduced dimethylation of (K9) of cardiac histone H3 as compared with db/db mice with normal renal function or nondiabetic wild-type mice. This pattern suggests alterations in chromatin structure that favor gene transcription. In fact, hearts from unine-phrectomized db/db mice revealed increased mRNA expression of multiple cardiomyopathy-related genes together with cardiomyocyte hypertrophy. These data suggest that renal failure alters cardiac histone H3 epigenetics, which foster cardiomyocyte hypertrophy in type 2 diabetes. (Am J Pathol 2010,176:1079-1083 DOI: 10.2353/ajpath.2010.090528)